The goal of this Program Project is in-depth analysis of normal and deregulated function of two novel genes recently cloned by us from IG gene-associated chromosome translocations in diffuse lymphoma with a large cell component (DLLC), clinically the most significant form of NHL. One, BCL6, is a zinc finger transcription factor mapped to chromosome band 3q27. BCL6 is altered by rearrangement in its 5' non-coding region in about 30% of DLLC and about 50% of follicular lymphomas (FL). Recent studies showed that in about 70% of DLLC and about 50% of FL, the BCL6 gene is also altered by multiple, often bi-allelic, mutations clustering in its %' non-coding region. These mutations are somatic in origin and independent of rearrangement by chromosome translocation. Our goals for BCL6 studies are represented by three projects in this Program Project which address the following issues: (1) mechanism, consequence, and role in NHL development of BCL6 and cytokine signaling, and (3) POK proteins in ontogenesis, lymphopoiesis, and lymphomagenesis. BCL8 has just been identified by virtue of its rearrangement with IGH gene in a DLLC by way of a chromosome translocation. It maps to 15q11-13. The goal of the final project in this Program Project is to investigate the structure and function of normal BCL8 and the mechanism and consequence of its alteration to NHL development. The studies proposed are designed to gain insights into the normal and abnormal function of BCL6 and BCL8 genes. Such insights are essential to understand the roles of these genes in normal mammalian development and human tumorigenesis. The four projects will be aided by an Administrative Core and a Mouse Molecular Pathology Core.